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An Open Label Study of LMI070 in Type 1 Spinal Muscular Atrophy (SMA)

This study is ongoing, but not recruiting participants.
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )
ClinicalTrials.gov Identifier:
NCT02268552
First received: October 1, 2014
Last updated: January 24, 2017
Last verified: January 2017
  Purpose
An open-label, multi-part, first-in-human study of oral LMI070 in infants with Type 1 spinal muscular atrophy. The purpose of this study is to evaluate the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD) and efficacy after 13 weeks; and to estimate the Maximum Tolerated Dose (MTD) and optimal dosing regimen of orally administered LMI070 in patients with Type 1 SMA.

Condition Intervention Phase
Spinal Muscular Atrophy Drug: LMI070 Phase 1 Phase 2

Study Type: Interventional
Study Design: Intervention Model: Single Group Assignment
Masking: No masking
Primary Purpose: Treatment
Official Title: An Open Label Multi-part First-in-human Study of Oral LMI070 in Infants With Type 1 Spinal Muscular Atrophy

Resource links provided by NLM:


Further study details as provided by Novartis ( Novartis Pharmaceuticals ):

Primary Outcome Measures:
  • Parts 1 & 2 Safety & Tolerability [ Time Frame: 13 weeks ]

    To evaluate the effect of LMI070 on the following;

    • Number of adverse events reported at all dose levels
    • Changes from baseline in existing and newly reported findings on physical examination
    • Changes from baseline in Hematology, blood chemistry and urinalysis results at all dose levels
    • Changes from baseline in vital signs at all dose levels
    • Changes from baseline on existing or newly reported ophthalmologic findings at all dose levels
    • Changes from baseline on existing or newly reported cardiac function at all dose levels
    • Changes from baseline in existing and newly reported neurological findings at all dose levels
    • Changes from baseline in existing and newly reported neurophysiological findings at all dose levels


Secondary Outcome Measures:
  • Changes in Growth Parameters from baseline [ Time Frame: Screening, Day 1, Day 8 to Day 85 & End of Study ]
    To evaluate the effect of LMI070 on the following growth measurements; - Body Weight & Length - Head & Chest Circumference

  • Changes in respiratory function from baseline [ Time Frame: Baseline, Day 8 to Day 85 & End of Study ]

    To evaluate the effect of LMI070 on respiratory function as change from Baseline by measurement of the following;

    • Infant cry vital capacity (optional)
    • Pulse oximetry
    • Respiratory rate
    • Paradoxical breathing assessment
    • Chest circumference during quiet breathing

  • Changes in Infant motor development from baseline [ Time Frame: Baseline, Day 36, Day 85 + End of Study ]
    To evaluate the effect of LMI070 on Infant Motor Development as in change from Baseline

  • Collect pharmacokinetic data from single and repeated dosing [ Time Frame: Part 1 Day 1 (Pre-dose + 1, 2, 4, 8 & 24 hours post-dose) and Days 2, 3, 5, 8, 29, 43 Part 2 Day 1 (Pre-dose + 1, 2, 4, 8 & 24 hours post-dose) and Days 2, 3, 5, 8, 29, 43, 57 (Pre-dose + 2, 4, 8 & 24 hours post-dose), 59, 62 ]
    To evaluate LMI070 pharmacokinetics in plasma after single and repeated doses of LMI070 by determination of AUC & Cmax

  • In addition to the above for Part 2 - Changes in motor and developmental milestones from baseline [ Time Frame: Baseline, Day 15, Day 36, Day 57, Day 88 + End of Study ]
    To evaluate the efficacy of LMI070 on motor and development milestones using the CHOP INTEND Infant Motor Scale

  • In addition to the above for Part 2 - Changes in Ulnar Nerve Compound Motor Action Potential (CMAP) from baseline [ Time Frame: Baseline, Day 88 + End of Study ]
    To evaluate the efficacy of LMI070 on Ulnar Nerve Compound Motor Action Potential (CMAP) in terms of % increase from baseline

  • In addition to the above for Part 2 - Changes in motor and developmental milestones from baseline [ Time Frame: Screening, Baseline, Day 1to Day 88 + End of Study ]
    To evaluate the efficacy of LMI070 on motor and development milestones by physical examination including assessment of oral feeding, head control, rolling, sitting up


Estimated Enrollment: 42
Study Start Date: April 2015
Estimated Study Completion Date: August 2017
Estimated Primary Completion Date: August 2017 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: LMI070
LMI070 Treatment
Drug: LMI070

Detailed Description:

This is an open-label, multi-part, first-in-human, proof of concept study in infants with Type 1 spinal muscular atrophy who have exactly 2 copies of SMN2, to evaluate safety, tolerability, PK, PD and efficacy of oral LMI070 after 13 weeks treatment.

Parts 1 and 2 are intended to be non-confirmatory. In Part 1 of the study, patients will be dosed once weekly with LMI070. The LMI070 dose will be escalated in subsequent cohorts until MTD is determined or when sufficient PK results confirm that the MTD cannot be reached due to a potential pharmacokinetic plateau at higher doses. A decision to dose escalate the next cohort will be made after safety data have been collected for 14 days following the first dose (14-day DLT window). PK will be used to confirm that there is no accumulation of the compound. Part 2 of the study will enroll new patients into one of up to 3 dosing regimens (depending on the results of Part 1) for 12 weeks. Patients who complete the first 13 weeks of Part 1 and are, in the opinion of the Investigator and Sponsor benefiting and/or tolerating LMI070, may continue treatment with higher doses of LMI070 that have been shown to be well tolerated.

  Eligibility

Ages Eligible for Study:   1 Month to 7 Months   (Child)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Written informed consent must be obtained from the parent / guardian before any assessment is performed.
  • Type 1 SMA, diagnosed clinically, with symptom onset <6 months of age and genetic confirmation of mutations in both alleles of the SMN1 gene, and with SMN2 copy number of 2.
  • Best supportive care in place and stable for at least 14 days before screening.
  • Age at screening between 1 and 7 months
  • Must be able to demonstrate antigravity strength in both biceps.
  • Must have or agree to have placement of feeding tube for enteral access via nasogastric (NG), nasojejunal (NJ), percutaneous gastrostomy (PEG), or percutaneous jejunostomy (PEJ) tube for dosing LMI070 (Part 1 only and for patients who cannot be administered orally ; tube may be removed between doses).
  • At birth gestational age >32 weeks and body weight at birth >2 kg.
  • Must live within 2 hours drive of study center. Clearance should be obtained from the site investigator and sponsor if the patient resides more than 2 hours ground travel from the study center
  • Able to complete all study procedures, measurements and visits; and parent or guardian/subject has adequately supportive psychosocial circumstances, in the opinion of the Site Investigator.

Exclusion Criteria:

  • Use of other investigational drugs within 14 days.
  • Neurologic, or neuromuscular conditions other than SMA.
  • Anemia, leukopenia, neutropenia or thrombocytopenia
  • Hepatic dysfunction
  • Age adjusted renal dysfunction
  • Clinically significant abnormalities in hematology or clinical chemistry parameters, as assessed by the Site Investigator, at screening that would render the subject unsuitable for inclusion
  • Intractable seizure disorder (other than inactive febrile seizures).
  • Persistent (in the opinion of the Investigator) hypoxemia (O2 saturation awake <92% or O2 saturation asleep <91%, without ventilation support) or requiring oral suctioning >2 per day, or presence of a tracheostomy.
  • Presence of an untreated or inadequately treated active infection requiring systemic antiviral or antimicrobial therapy at any time during the screening period.
  • Current diagnosis of cardiac and/or vascular abnormalities or ECG abnormalities (such as long QT, heart block or Torsade's) indicating significant risk of safety for infant patients participating in the study such as: Concomitant clinically significant pediatric cardiac arrhythmias, e.g. sustained ventricular tachycardia, and clinically significant second or third degree AV block
  • Prohibited Concomitant Medications
  • Excluding SMA, any medically unstable condition including cardiomyopathy, hepatic dysfunction, kidney disorder, endocrine disorder, GI disorders, prematurity of <32 weeks gestation, metabolic disorders, severe respiratory compromise and significant brain abnormalities or injuries including hypoxic-ischemic encephalopathy.
  • Acute or ongoing medical condition that, according to the Site Investigator and discussed with sponsor, would interfere with the conduct and assessments of the study. Examples are medical disability other than SMA that would interfere with the assessment of safety or would compromise the ability of the subject to undergo study procedures including be assessed by CHOP INTEND motor scale, changes in hematologic parameters or gastrointestinal dysfunction that would compromise the ability of adequate assessment of safety.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT02268552

Locations
Belgium
Novartis Investigative Site
Gent, Belgium, 9000
Novartis Investigative Site
Leuven, Belgium, 3000
Denmark
Novartis Investigative Site
Copenhagen, Denmark, 2100 O
Germany
Novartis Investigative Site
Essen, Germany, 45147
Novartis Investigative Site
Freiburg, Germany, 79106
Italy
Novartis Investigative Site
Roma, ITA, Italy, 00165
Novartis Investigative Site
Milano, MI, Italy, 20133
Sponsors and Collaborators
Novartis Pharmaceuticals
  More Information

Responsible Party: Novartis Pharmaceuticals
ClinicalTrials.gov Identifier: NCT02268552     History of Changes
Other Study ID Numbers: CLMI070X2201
Study First Received: October 1, 2014
Last Updated: January 24, 2017

Keywords provided by Novartis ( Novartis Pharmaceuticals ):
Type 1 Spinal Muscular Atrophy

Additional relevant MeSH terms:
Atrophy
Muscular Atrophy
Muscular Atrophy, Spinal
Pathological Conditions, Anatomical
Neuromuscular Manifestations
Neurologic Manifestations
Nervous System Diseases
Signs and Symptoms
Spinal Cord Diseases
Central Nervous System Diseases
Motor Neuron Disease
Neurodegenerative Diseases
Neuromuscular Diseases

ClinicalTrials.gov processed this record on June 27, 2017